This invention relates generally to the fields of biochemistry and medicine. More particularly, the present invention relates to compositions for use in imaging cancer or infectious disease.
Imaging of cellular proliferation in vivo using radiolabeled analogues of nucleosides such as .sup.13 I!-IUdR and .sup.11 C!-thymidine is plagued by extensive catabolism of the parent compounds following intravenous administration, limiting uptake into the DNA of tumor tissues. Such catabolic events include dehalogenation, cleavage of the sugar moieties from the base, and ring opening of the base. In vivo assessment of such events requires complex mathematical models to interpret kinetic data obtained in imaging studies.
Mathematical models currently being designed to interpret positron emission tomography (PET) kinetic data obtained from .sup.11 C! thymidine studies in tumors are generally cumbersome, in large measure due to the presence of significant levels of short-term catabolism of thymidine with subsequent production of several radiolabeled byproducts in plasma and tissue Martiat P. H., Ferrant A., Labar D., et al. (1988) In vivo measurement of carbon-11 thymidine uptake in non-Hodgkin's lymphoma using positron emission tomography. J. Nucl. Med. 29, 1633-1637; Shields A. F., Larson S. M., Grunbaum A., and Graham M. M. (1984). Short-term thymidine uptake in normal and neoplastic tissues: Studies for PET. J. Nucl. Med. 25, 759-764; Shields A. F., Coonrod D. U., Quakenbush R. C., et al. (1987) Cellular sources of thymidine nucleotides: Studies for PET. J. Nucl. Med. 28, 1435-1440; Wong C. Y. O., Yue N., Chan B., et al. (1994) .sup.11 C!-Thymidine PET imaging as a measure of DNA synthesis rate: A preliminary quantitative study of human brain glioblastoma. J. Nucl. Med. 35, 9P; Mankoff D. A., Graham M. M., and Shields A. F. (1994a) Graphical analysis method for estimating blood-to-tissue transfer constants for tracers with labeled metabolites. J. Nucl. Med. 35, 34P, 1994; Mankoff D. A., Shields A. F., Lee T. T., and Graham M. M. (1994b) Tracer kinetic model to quantitative imaging of thymidine utilization using .sup.11 C!-thymidine and PET. J. Nucl. Med. 35, 138P!. Though potentially less complex, modeling of the kinetic behavior of ring labeled thymidine is likewise non-trivial Shields ASF., Graham M. M., and O'Sullivan F. (1992) Use of .sup.11 C!-thymidine with PET and kinetic modeling to produce images of DNA synthesis. J. Nucl. Med. 33, 1009-1010; Mankoff et al., 1994a,b, supra!. In the case of imaging studies with radioiodinated IUdR using conventional nuclear medicine techniques, in addition to significant dehalogenation it has also been demonstrated that UdR, once formed, may be converted to TdR in mammalian systems and subsequently incorporated into DNA Commerford S. L. and Joel D. D. (1979) Iododeoxyuridine administered to mice is de-iodinated and incorporated into DNA primarily as thymidylate. Biochem. Biophys. Res. Comm. 86, 112-118!.
The short-term catabolism of .sup.11 C and .sup.14 C-methyl!-thymidine have been extensively studied Conti P. S., Hilton J., Magee C. A., and Anderson J. H. (1989) Tumor imaging with positron-emission tomography (PET) and .sup.11 C!-thymidine: Determination of radiolabeled thymidine metabolites by high pressure liquid chromatography (HPLC) for kinetic data analysis. Radiology 173, P402; Conti P. S., Hilton J., Magee C. A., and Anderson J. H. (1990) Analysis of nucleoside metabolism during positron emission tomography (PET) imaging studies of brain tumors with carbon-11 labeled thymidine (TdR). 199th Meeting of American Chemical Society, Boston, Mass. April 22-27!. Such studies have demonstrated that significant catabolism occurs once thymidine has been administered intravenously, with the notable radiolabeled products being thymine, dihydrothymine, beta-ureidoisobutyric acid, and beta-aminoisobutyric acid. The latter constitutes the most abundant radiolabeled species in plasma and tissues by 10 minutes post-injection. While .sup.11 C!-CO.sub.2 is the most abundant radiolabeled species in plasma following administration of ring labeled thymidine Shields A. F., Kozell L. B., Link J. M., et al. (1990b) Comparison of PET imaging using .sup.11 C!-thymidine labeled in the ring-2 and methyl positions. J. Nucl. Med. 31, 794; Shields A. F., Swenson E. R., and Bassingthwaighte J. B. (1990c) Contribution of labeled carbon dioxide to PET imaging of .sup.11 C!-labeled compounds. J. Nucl. Med. 31, 909!, radiolabeled thymine, dihydrothymine, and beta-ureidoisobutyric acid also are present, albeit in lesser amounts. Despite its extensive catabolism, it has been demonstrated that .sup.11 C!-thymidine has utility in tumor imaging in both animal models and patients Larson S. M., Weiden P. L., Grunbaum A., et al. (1981) Positron imaging feasibility studies. I: Characteristics of .sup.3 H!-thymidine uptake in rodent and canine neoplasms: Concise Communication. J. Nucl. Med. 22, 869-874; Conti P. S., Kleinert E. L., Schmall B., et al. (1984a) Potential use of carbon-11 labeled thymidine (TdR) for studying the effect of therapy on prostatic adenocarcinoma in vivo. 32nd Annual Meeting of the Radiation Research Society, Orlando, Fla., March 25-29; Conti P. S., KIeinert E. L., Schmall B., Whitmore W. F., Jr. (1984b) Comparative uptake studies of radiolabeled thymidine in the Dunning R3327H fast-growing and R3327H slow-growing prostate adenocarcinomas in vivo. 79th Meeting of the American Urological Association, New Orleans, La., May 6-10; Conti, P. S., Schmall, B., Herr, H. W., et al. (1985) Carbon-11 labeled alpha-aminoisobutyric acid, 2-deoxy-D-glucose and thymidine as potential imaging agents for prostatic and renal malignancies. Surgical Forum 36, 635-637; Conti P. S., Camargo E. E., Grossman S. A., et al. (1991) Multiple radiotracers for evaluation of intracranial mass lesions using PET. J. Nucl. Med. 32, 954; Shields et al., 1984, 1987, 1990b,c, supra; Shields A. F., Lim K., Grierson J., et al. (1990a) Utilization of labeled thymidine in DNA synthesis: Studies for PET. J. Nucl. Med. 31, 337-342; Martiat et al. 1988, supra; Strauss L. G. and Conti P. S. (1991) The applications of PET in clinical oncology. J. Nucl. Med. 32, 623-648; Schmall B., Conti P. S., Schaeffer D. J., and KIeinert E. L. (1992) Tumor and organ biochemical profiles determined in vivo following uptake of a combination of radiolabeled substrates: Potential applications for PET. Amer. J Phys. Imag. 7 , 2-11; Wong et al. 1994, supra; Vander Borght T., Pauwels S., Lambotte L., et al. (1994) Brain tumor imaging with PET and 2-.sup.11 C!-thymidine. J. Nucl. Med. 35: 974-982!.
There is thus a long-felt need in the art for a suitable partially or non-catabolized imaging agent (e.g., nucleoside analog) for use in, e.g., tumor proliferation studies with PET. Except for limited catabolism, an ideal tracer should share the other in vivo characteristics of thymidine, including cell transport, phosphorylation by mammalian kinase, and incorporation into DNA. In particular, development of a partially or non-catabolized thymidine analog would greatly simplify imaging and modeling approaches and potentially provide higher tumor to target ratios due to more selective incorporation of radiotracer.
It is an object of the present invention to provide compositions and methods which do not suffer from the drawbacks of the heretofore-known compositions.